CN101861169B - Stabilisation of oily suspensions containing hydrophobic silicic acids - Google Patents

Stabilisation of oily suspensions containing hydrophobic silicic acids Download PDF

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CN101861169B
CN101861169B CN2008801166469A CN200880116646A CN101861169B CN 101861169 B CN101861169 B CN 101861169B CN 2008801166469 A CN2008801166469 A CN 2008801166469A CN 200880116646 A CN200880116646 A CN 200880116646A CN 101861169 B CN101861169 B CN 101861169B
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medicine
silicon stone
acid
polyoxyethylene
chemical compound
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CN101861169A (en
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I·希普
H-J·哈曼
S·科林
G·道比
K-J·斯蒂芬斯
R·丹尼尔斯
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Bayer Pharma AG
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

Abstract

The invention relates to the stabilisation of oil based fluidic suspensions containing a hydrophobic silicic acid, in addition to medicaments based on said type of suspensions.

Description

The stabilisation that comprises the oily suspension of hydrophobicity Silicon stone
The present invention relates to comprise hydrophobicity Silicon stone (
Figure GPA00001138960000011
) oil based fluids (fluid) suspension stabilisation and based on the medicine of such suspension.
Medicine based on the oils preparation can have various advantages, for example the stability of patient's toleration or active component.Yet, can be used for medicinal oils and can always not have in order for example to reduce or to avoid the necessary viscosity of active component sedimentation.Therefore, can be used for cosmetics although be used for increasing most of known substances of oils viscosity, they can not be applied in the medicine.Thereby for example, colloidal silica is used for the oils (US 2001-0006671, US4079131, WO 03-063877) that thickening is used for medicine.
In WO 2006/008640, in colloidal silica (Silicumdioxid) (hydrophilic Silicon stone), add nonionic emulsifier, so that active component moistening better in oils.
In WO 03/022254, colloidal silica, hydrophilic and hydrophobicity Silicon stone mix with hydrophilic polymer in oils, and said hydrophilic polymer is such as for example Macrogol 200 or polyvinyl alcohol.The interaction of said Silicon stone and said polymer is use, the raising yield point that is used for reducing Silicon stone and reduces shear viscosity.
FR 2790200 also mentions the hydrophobicity Silicon stone, but the clear and definite especially stabilizing agent that do not add.
WO 2006/061155 and WO 2006/061156 have not only described the hydrophilic Silicon stone in oils, and have described the hydrophobicity Silicon stone in oils.Wherein also can be used as general material and use for example nonionic surfactant or for example Macrogol 200.
It is very responsive for water or dampness that the shortcoming that the hydrophilic Silicon stone has in Oily preparation is them, and even absorption from the dampness of surrounding air.The result is that the viscosity of preparation increases and is no longer can reach given degree from the taking-up property of initial package for example.This is unacceptable in particular for medicine.If, for example, in the time of will being used for these preparations by the single dose container of plastics preparations, to consider especially that to the influence of the sensitivity of dampness because plastic containers are non-moistureproof, the preparation in filling containers absorbs dampness, viscosity possibly increase.In addition, compare with multi-dose container, in the single dose container, the surface area of preparation and the ratio of surrounding air are unfavorable especially.
Can overcome sensitivity through using the hydrophobicity Silicon stone to come stable suspension to avoid sedimentation to dampness.Yet the major defect of hydrophobicity Silicon stone is that long-time stability relevant with the settlement stability effect are poorer than the hydrophilic Silicon stone.The characteristics of poorer long-time stability are that the initial viscosity of Oily preparation reduces in several weeks or some months, this is unacceptable for medicine, because this can cause for example unwanted sedimentation.
Finding to contain the long-time stability of the Oily preparation of hydrophobicity Silicon stone unexpectedly can improve through adding amphiphilic compound significantly.When using the hydrophilic Silicon stone, this effect exists hardly.In the prior art, for the oily suspensions that comprises the hydrophobicity Silicon stone especially, also not describing should effect.
Therefore, the present invention relates to:
Amphiphilic species is used for the stable purposes that comprises the oil based fluids suspension of hydrophobicity Silicon stone.
Such fluid suspension is preferably used for pharmaceutical formulation.
Therefore, the invention further relates to:
Medicine is included in the oil binder:
A) active component
B) hydrophobicity Silicon stone
C) the ethylating chemical compound of polyoxy.
" oil base " refers to that corresponding suspension or relative medicine comprise oil binder (Grundlage).Natural (animal or plant), synthetic and semisynthetic oils or fat all can be used as oil binder.The example is soybean oil, Oleum helianthi, Oleum Gossypii semen, olive oil, Oleum Arachidis hypogaeae semen, safflower oil, Petiolus Trachycarpi oil, Oleum Brassicae campestris, Oleum Cocois, Semen Maydis oil or Oleum Ricini.Preferably use propylene glycol diesters, thin liquid shape (d ü nnfl ü ssig) paraffin or the Oleum sesami of medium chain triglyceride (having satisfied fatty acid, the triglyceride of preferably octanoic acid and capric acid), caprylic/capric; In these, the propylene glycol diesters of medium chain triglyceride and caprylic/capric is particularly preferably used.
The usage ratio of said oil binder typically is the 99-72 weight % based on relevant suspension or final medicine, preferred 99-88 weight %, preferred especially 97-92 weight %.
Said suspension can have different viscosity, thereby, all can consider from thin liquid shape suspension to paste in principle.Preferably provide the liquid system that comprises thin liquid shape and magma shape (dickfl ü ssig) system, as long as they are still in they deadweight current downflow.Preferred fluid system has yield point, and promptly these systems flow after shearing (for example through jolting).In many cases, active component can not or can not be dissolved in the fluid base material fully, so active component also must suspend.For this reason, use the hydrophobicity Silicon stone to be used for stable suspension and avoid sedimentation as thickening agent.
The hydrophobicity Silicon stone is not by the Silicon stone of water-wet; This means that they swim on the water surface.The mixed oxide of the hydrophobization of silicon dioxide and aluminium oxide also is suitable, but hydrophobic pure silicon stone is preferred.They mix generation through the hydrophilic Silicon stone with silane (halogenated silanes, alkoxy silane, silazane, siloxanes).Wherein silanol is next alkylating by alkyl, and said alkyl preferably has 18 carbon atoms at the most, particularly preferably has 8 carbon atoms at the most, very particularly preferably has 4 carbon atoms, particularly methyl at the most.The instance of the silane that is used to prepare is a HMDS, or dimethyldichlorosilane preferably.Suitable hydrophobicity Silicon stone can be derived from settled, high dispersive, pre-embossed or fumed silica, preferred fumed silica.For example; The reaction of hydrophilic Silicon stone and dimethyldichlorosilane produces hydrophobicity Aerosil, has proprietary name R972; Its degree of methylating that has is 66%-75% (measuring through all the other silanol of titration).
The usage ratio of hydrophobicity Silicon stone in preparation typically is 0.1-10 weight %, is preferably 0.5-5 weight %, particularly preferably is 1.5-4.0 weight %.
Amphiphilic compound is made up of polarity (hydrophilic) and nonpolar (hydrophobicity) part.Typical amphiphilic species is fatty acid, surfactant and phospholipid.Active component also can be an amphipathic characteristic.Like this, for example quinolinones or fluoroquinolone all are amphipathic.Said molecule has acidic-group and basic group.Said acidic-group can be the deprotonation form, thereby has negative charge; Said basic group can be a protonated form, thereby has positive charge.Each live part of said molecule all is a high polarity and hydrophilic, and the remainder of molecule is low polar, thereby hydrophobicity is stronger.
In context of the present invention, preferred amphiphilic compound is the chemical compound of polyoxy ethylization (polyoxyethyliert).The ethylating chemical compound of polyoxy is also referred to as the chemical compound of polyethoxylated (ployethoxyliert), is for example through with the ethylene oxide prepared in reaction.They have one or more formulas-[O-CH 2-CH 2]-be connected to each other (
Figure GPA00001138960000032
) the unit.The ethylating chemical compound of the polyoxy that can mention is especially:
The ethylating chemical compound of non-ionic amphipathic polyoxy such as
● poloxamer, preferably, molal weight is 100 to 5000g/mol, particularly preferably molal weight is 1000 to 3500g/mol.Poloxamer is the INN of the block copolymer of ethylene oxide and methyl oxirane.
● polyoxyethylene fatty acid glyceride, also belong to nonionic emulsifier, Polyethylene Glycol castor oil acid glyceride for example preferably,
● polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 20 Arlacel-80s for example preferably,
● polyoxyethylene fatty acid, such as Polyethylene Glycol 15 hydroxy stearic acid esters (=Solutol HS15 can obtain through 15mol ethylene oxide and the reaction of 1mol 12-hydroxy stearic acid)
● the polyoxyethylene aliphatic alcohol, such as hydroxyl polyethoxy dodecane.
Fatty acid or aliphatic alcohol are represented especially has at least 6 carbon atoms, is no more than the respective compound of 30 carbon atoms usually.
The ethylating chemical compound of said amphiphilic compound, particularly polyoxy usage ratio in preparation typically is 0.001-0.15 weight %, is preferably 0.005-0.09 weight %, particularly preferably is 0.005-0.08 weight %, particularly 0.01-0.07 weight %.
Oil-based suspension of the present invention preferably is applied in the medicine.Thereby it comprises one or more active constituents of medicine.
The instance that can mention is an anti-infectives; These are especially for having the chemical compound of antibacterial activity, such as PCs, cephalosporins, aminoglycoside, sulfonamides, and quinolones particularly.
Quinolones; Preferred FQNS, particularly the instantiation like the quinolones that disclosed chemical compound: US 4670444 (Bayer AG), US 4472405 (Riker Labs), US 4730000 (Abbott), US 4861779 (Pfizer), US 4382892 (Daiichi), US 4704459 (Toyama) can mention in following file is pipemidic acid (
Figure GPA00001138960000041
) and nalidixic acid (
Figure GPA00001138960000042
); The instance of the FQNS that can mention is: benzene Flucloxacillin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, Marbofloxacin, MOXIFLOXACIN, norfloxacin, ofloxacin, orbifloxacin, first Flucloxacillin, temafloxacin, tosufloxacin, Sarafloxacin, Sparfloxacin.
Preferred FQNS type of compounds is formula (I) or (II) those:
Wherein
X is hydrogen, halogen, C 1-4-alkyl, C 1-4-alkoxyl, NH 2,
Y is the group of following structure
Wherein
R 4For randomly by hydroxyl-or methoxyl group-substituted straight or branched C 1-C 4-alkyl, cyclopropyl, have the acyl group of 1 to 3 C atom,
R 5Be hydrogen, methyl, phenyl, thienyl or pyridine radicals,
R 6Be hydrogen or C 1-4-alkyl,
R 7Be hydrogen or C 1-4-alkyl,
R 8Be hydrogen or C 1-4-alkyl,
With
R 1Be alkyl (it has 1 to 3 carbon atom), cyclopropyl, 2-fluoro ethyl, methoxyl group, 4-fluorophenyl, 2,4 difluorobenzene base or methylamino,
R 2For hydrogen or randomly by the substituted alkyl with 1 to 6 carbon atom of methoxyl group or 2-methoxy ethoxy and cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxy carbonyl methyl, oxy acid methyl neopentyl,
R 3For hydrogen, methyl or ethyl and
A be nitrogen ,=CH-,=C (halogen)-,=C (OCH 3)-,=C (CH 3)-or=C (CN),
B is an oxygen, randomly by methyl or phenyl-substituted=NH or=CH 2,
Z is=CH-or=N-,
And available salt of pharmacy and hydrate.
Formula (I) and chemical compound (II) can exist with their racemate or enantiomeric form.
The chemical compound of formula (I) preferably
Wherein
A is=CH-or=C-CN,
R 1For randomly by the substituted C of halogen 1-C 3-alkyl or cyclopropyl,
R 2Be hydrogen or C 1-4-alkyl,
Y is the group of following structure
Figure GPA00001138960000061
Wherein
R 4For randomly by the substituted straight or branched C of hydroxyl 1-C 3-alkyl, have the oxa alkyl (Oxalkyl) of 1 to 4 C atom,
R 5Be hydrogen, methyl or phenyl,
R 7Be hydrogen or methyl,
R 6And R 8Be hydrogen,
And available hydrate of pharmacy and salt.
Particularly preferably be the chemical compound of formula (I)
Wherein
A is=CH-or=C-CN,
R 1Be cyclopropyl,
R 2Be hydrogen, methyl or ethyl,
Y is the group of following structure
Figure GPA00001138960000071
Wherein
R 4Be methyl, randomly by the substituted ethyl of hydroxyl,
R 5Be hydrogen or methyl,
R 7Be hydrogen or methyl,
R 6And R 8Be hydrogen,
And available salt of pharmacy and hydrate.
Suitable salt is available acid-addition salts of pharmacy and basic salt.
The instance of the available salt of pharmacy is hydrochloric acid, sulphuric acid, acetic acid, glycolic, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, pounce on the salt of acid (
Figure GPA00001138960000072
), glutamic acid or Aspartic Acid.Chemical compound of the present invention also can be bonded to acidity or alkaline ion exchanger.The available basic salt of the pharmacy that can mention is an alkali metal salt, for example sodium salt or potassium salt, alkali salt, for example magnesium salt or calcium salt; Zinc salt, silver salt and guanidine (Guanidinium) salt.
Hydrate refers to the hydrate of fluoroquinolone compounds self and the hydrate of its salt.
The chemical compound of preferred especially fluoroquinolone compounds that can mention in WO 97/31001, describing; 8-cyanic acid-1-cyclopropyl-7-((1S particularly; 6S)-2; 8-diazabicylo [4.3.0] nonanal-8-group)-and 6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (Pradofloxacin (Pradofloxacin)), it has following formula
Figure GPA00001138960000073
Pradofloxacin preferably uses with its trihydrate forms.
Especially preferably use enrofloxacin (Enrofloxacin) in addition:
1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid
Figure GPA00001138960000081
Except enrofloxacin and Pradofloxacin, also mention Marbofloxacin, orbifloxacin, difloxacin, ofloxacin and ibafloxacin as preferred quinolinones anti-infectives.
The instance of PCs (Penicilline) is penicillin (Benzylpenicillin), ampicillin, amoxicillin, oxazacillin, piperacillin, ticarcillin.
The instance of cephalosporins is cefalexin, cefadroxil, cefazolin sodium, cefoxitin, ceftiofur.
Can mention for example erythromycin, spiramycin, tylosin, the tilmicosin of being as macrolide.
The sulfonamide that can mention is for example trimethoprim and sulfadiazine (preferably using with combining form).
The aminoglycoside that can mention is gentamycin, kanamycin, streptomycin, neomycin and spectinomycin.
The further antibiotic that can mention is the lincosamide clindamycin.
Less preferred anti-infectives in context of the present invention is derived from silver, for example collargol, silver nitrate or silver sulfadiazine.Yet these can be with one of above-described anti-infectives and/or randomly use with the adrenocortical hormone combination.
The usage ratio of said anti-infectives typically is the 0.001-6 weight % based on final medicine, preferred 0.01-1.0 weight %, preferred especially 0.1-0.8 weight %.
The further active constituents of medicine that can mention is an antifungal agent, such as for example imidazoles or triazole, ketoconazole, enilconazole, econazole, and for example clotrimazole, miconazole or bifonazole especially.
The usage ratio of said antifungal typically is the 0.01-10 weight % based on final medicine, preferred 0.1-5 weight %, preferred especially 0.5-2 weight %.
Further suitable active constituents of medicine is for example adrenocortical hormone.The instance that can mention is hydrocortisone, prednisolone, betamethasone, mometasone, clobetasone, flumetasone; Preferred betamethasone, triamcinolone, particularly dexamethasone.
The usage ratio of said adrenocortical hormone typically is the 0.001-2.0 weight % based on final medicine, preferred 0.005-0.5 weight %, preferred especially 0.05-0.2 weight %.
Further suitable active constituents of medicine is a triazines, in particular formula (I) or chemical compound (II):
Figure GPA00001138960000091
Wherein
R 1Be R 3-SO 2-or R 3-S-,
R 2Be alkyl, alkoxyl, halogen or SO 2N (CH 3) 2And
R 3Be haloalkyl,
R 4And R 5Be independently of one another hydrogen or Cl and
R 6Be fluorine or chlorine,
And physiology's salt of allowing.
As everyone knows, triazines itself is mentioned the triazinetrione class, such as for example toltrazuril and ponazuril and triazinediones class, such as for example clazuril, diclazuril and letrazuril as active component antagonism coccidium infection.
Said triazinediones class is provided by formula (II):
Clazuril (R in the formula (II) 4=Cl, R 5=H, R 6=Cl)
Letrazuril (R in the formula (II) 4=Cl, R 5=Cl, R 6=F) and
Diclazuril (R in the formula (II) 4=Cl, R 5=Cl, R 6=Cl)).
These 1,2,4-triazinediones apoplexy due to endogenous wind is diclazuril most preferably.
Particularly preferably be the triazinetrione class of formula (I) as active component according to the present invention:
R 2Being preferably and having the alkyl or the alkoxyl of 4 carbon atoms at the most separately, particularly preferably is methyl, ethyl, n-pro-pyl, isopropyl.
R 3Being preferably the perfluoroalkyl with 1 to 3 carbon atom, particularly preferably is trifluoromethyl or pentafluoroethyl group.
The instance of the triazinetrione class of preferred especially formula (I) is:
Toltrazuril (R 1=R 3-S-, R 2=CH 3, R 3=CF 3)
Ponazuril (R 1=R 3-SO 2-, R 2=CH 3, R 3=CF 3)
In these, toltrazuril is most preferred.
For all medicinal active ingredients-as above-mentioned for quinolones describe in detail-can use corresponding officinal salt, hydrate, solvate and optional various modes of texturing.
Optically active substance can use with their stereoisomer or stereoisomer mixture enantiomer for example pure or enrichment or with the form of raceme.
In suspension of the present invention or medicine, under various situation, active component can exist individually or use with other active component combination.
In a preferred embodiment, can regulate preparation of the present invention, make it have thixotropic nature, this is meant that when jolting it becomes the thin liquid shape, and viscosity increases once more when static.This causes the satisfied taking-up property from initial package, and quick reconfiguration; When auditory meatus administration for example, this is favourable, makes the preparation of administration be retained in the ear, and can for example not dish out owing to shaking the head.The thixotroping preparation be through in the preparation base material (fluid, oil binder) add suitable additive preparation, if said fluid base material itself is not thixotropic.Such additive is generally suspension stabilizer or thickening agent, such as for example high dispersive silicon dioxide.Thixotropic degree can be regulated through changing concentration targetedly.
Said preparation can comprise additive compatible on other the conventional pharmaceutical and auxiliary agent.The instance that can mention does
● further thickening agent is optional usually, but randomly can use.The instance of the further thickening agent that can mention is: cellulose derivative, such as methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, microcrystalline Cellulose; Bentonite, Kaolin, pectin, starch, modified starch; Wax, agar, paraffin, gelatin, alginate; Polyvinyl pyrrolidone, crospovidone, spermol, stearate/ester be such as for example magnesium stearate, zinc stearate or tristerin, saturated or unsaturated LCFA (C 8-C 24), high molecular weight polyethylene glycol (for example Macrogol 2000) and Silicon stone,
● antiseptic; Such as for example carboxylic acids (sorbic acid, propanoic acid, benzoic acid, lactic acid), phenol (cresol, right-hydroxy benzenes acid esters is such as methyl hydroxybenzoate, propylparaben etc.), aliphatic alcohol (benzyl alcohol, ethanol, butanols etc.), quaternary ammonium compound (benzalkonium chloride, cetylpyridinium chloride)
● antioxidant, such as for example sulphite (sulfurous acid Na, inclined to one side bisulfite Na), organic sulfur compound (cystine, cysteine, mercaptamine, methionine, thioglycerol, TGA, 2-mercaptopropionic acid), phenol (tocopherols, for example vitamin E and vitamin E TPGS (d-alpha-tocopherol cetomacrogol 1000 succinate)), Butylated hydroxyanisole, butylated hydroxytoluene, gallic acid (propyl gallate, gallateoctylester and lauryl gallate), organic acid (ascorbic acid, citric acid, tartaric acid, lactic acid) and salt and ester.
● wetting agent or emulsifying agent, such as for example soap, aliphatic alkyl sulfate, aliphatic alkyl sulfonate, linear alkylbenzene sulfonate (LAS), aliphatic alkyl polyethylene glycol ether sulfate, aliphatic alkyl polyglycol ether, alkyl phenol polyglycol ether, alkyl polyglycoside, fatty acid N-methyl glucoside amine, Polysorbate, fatty acid esters of sorbitan, lecithin and poloxamer.
● pharmaceutically acceptable coloring agent, such as for example ferrum oxide, carotenoid etc.
● said preparation also can comprise the cosolvent that reduces viscosity.The usage ratio of these materials is generally 0.1 to 40 weight %, preferred 1 to 10 weight %.The instance of the cosolvent that can mention is: the alcohol of pharmaceutically compatible, and such as ethanol or benzyl alcohol, dimethyl sulfoxine, ethyl lactate, ethyl acetate, glyceryl triacetate, N-Methyl pyrrolidone, glycerol formal, propylene glycol carbonate, benzyl benzoate, Tetrahydrofurfuryl polyethylene glycol ether (glycofurol), dimethyl acetylamide, 2-Pyrrolidone, acetone glycerol, glycerol and Polyethylene Glycol.The mixture of aforementioned solvents also can be used as cosolvent and uses.
● water
● operable spreading agent is hexyl dodecanol, oleic acid decyl ester, dibutyl adipate, polydimethylsiloxane, castor oil acid glyceride, octyldodecanol, octyl stearate, two n-nonanoic acid propylene glycol esters especially, preferred isopropyl myristate or isopropyl palmitate.
● penetration enhancer (or penetration enhancers) improves the transdermal administration of medicine; It is known in principle (referring to for example Dermatopharmazie in the prior art; WissenschaftlicheVerlagsgesellschaft mbH Stuttgart, the 6th chapter, 2001).The instance that can mention is to sprawl oils, such as isopropyl myristate, n-nonanoic acid dipropylene glycol ester, silicone oil and with copolymer, fatty acid ester (for example oleic acid oil base ester), triglyceride, aliphatic alcohol and the linolein of polyethers.Also can use DMSO, N-Methyl pyrrolidone, 2-Pyrrolidone, dipropylene glycol monomethyl ether, octyldodecanol, oil base polyethyleneglycol glyceride or lauric acid propylene glycol ester.
Said preparation can be dispersed in the base material through the active component that will dissolve or suspend or auxiliary agent and prepare.Randomly, in order to disperse to use homogenizer or high pressure homogenizer.The addition sequence of various compositions can change according to preparation.After all preparation compositions have all been disperseed, with depositing or directly put into initial package in the middle of the final preparation.
In principle, all possible initial package all is suitable for suspension of the present invention or medicine.In a preferred embodiment, use the single dose container as initial package.These container loadings 0.1-0.5ml, preferred 0.2-0.4ml, preferred especially 0.3-2.0ml volume are as the taken out content of preparation.
Medicine of the present invention is applicable to the human and animal usually.They preferably are applied in and are used for useful animal (Nutztier), breeding animal (Zuchttier), zoo animal, laboratory animal, laboratory animal and companion animals, particularly mammal in animal feeding and the animal breeding.
Said useful animal and breeding animal comprise mammal, such as cattle for example, horse, sheep, pig, goat, camel, Babalus bubalis L., donkey, rabbit, fallow deer, reinder, fur-bearing animal such as for example ermine, squirrel, racoon and birds such as for example chicken, goose, turkey, duck, pigeon and Ostriches.The instance of preferred useful animal is cattle, sheep, pig and chicken.
Said laboratory animal and laboratory animal comprise that Canis familiaris L., cat, rabbit and rodent are such as mice, rat, Cavia porcellus and golden hamster.Companion animals comprises the Canis familiaris L. domestic and zoo raised, cat, horse, rabbit, rodent such as golden hamster, Cavia porcellus, mice, and reptile, Amphibian and birds.
Medicine of the present invention preferably is applied to companion animals, is used for Canis familiaris L. and cat especially especially.
Application can be implemented with prevention and therapeutic modality.
In principle, medicine described herein all is suitable for all possible administering mode such as skin for example, oral, rectum, vagina or nasal-cavity administration.They for example are suitable for topical especially in auditory meatus.
Therefore, described preparation be particularly suitable for health treatment Canis familiaris L. and cat the auditory meatus disease such as external otitis.For this purpose, they preferably are loaded in the single dose container as initial package.Should stress especially that said preparation can be taken out fully with reproducing.If in suspension preparation, use thickening agent, the sedimentation of its composition that possibly prevent usually to suspend.The thixotroping preparation is particularly advantageous; Because after jolting single dose container; Said preparation can-even the concentration of active component is low-but well reproduced ground takes out especially because thixotropy and single dose container, said preparation can simply wholesomely be administered in the animal ear; Yet it can for example not dished out owing to common shaking the head.Expect that also said preparation has the good behavior of sprawling, because said preparation should be distributed in the auditory meatus well after administration.
The medicine that is used for the administration auditory meatus can preferably comprise antibiotic described above, adrenocortical hormone or antifungal agent.The combination of antibiotic and adrenocortical hormone is preferred, and the triple combination of antibiotic, adrenocortical hormone and antifungal agent is preferred especially.Above-mentioned statement about the preferred embodiment of corresponding active component combination also is applicable to this application.
The instance of the preferred especially active component combination that can mention is: Pradofloxacin, clotrimazole and dexamethasone (being preferably the form of its acetas) and enrofloxacin, bifonazole and dexamethasone (being preferably the form of its acetas).
The dynamic (dynamical) mensuration of sedimentation
Fig. 1 has described the sedimentation kinetics of the preparation that contains the hydrophobicity Silicon stone.Measure through the measuring light diffraction with so-called Lumifuge.Said sedimentation kinetics with the sedimentation of preparation be described on the y axle (" interfacial level (Interphase Height) ") and will be in centrifugal force field the open-assembly time to gravity be described in (with a hour expression) on the x axle.Under the gravity that uses, the preparation with 100% interfacial level does not have sedimentation, and the preparation ratio of 80% interfacial level gets severe like the preparation sedimentation with 90% interfacial level and for example have.
The preparation of said measurement, the preparation of embodiment 13 is included in hydrophobicity Silicon stone (Aerosil R972, methylated Silicon stone is from Degussa) and toltrazuril in the thin liquid shape paraffin especially.Minimum curve does not comprise the chemical compound of the polyethoxylated of adding; And other curve comprises the chemical compound as the polyethoxylated of additive; Particularly from the poloxamer (Pluronic PE8100, Pluronic PE3100 and Pluronic RPE3110) of BASF.
Obviously the preparation that contains the hydrophobicity Silicon stone and do not add the chemical compound (poloxamer) of polyethoxylated demonstrates minimum curve.All other preparations, it also comprises the chemical compound (as above known various poloxamers) of the polyethoxylated of adding except comprising the hydrophobicity Silicon stone, all be in obvious higher position.Thereby, to compare with the preparation of the chemical compound that does not add polyethoxylated, the sedimentation character of preparation of chemical compound that contains the polyethoxylated of adding has been improved (that is, preventing sedimentation) significantly.
Embodiment
The percentage ratio data of preparation described herein are represented with weight/volume.The medium chain triglyceride that uses is the triglyceride of caprylic/capric, for example from
Figure GPA00001138960000141
812 of Sasol/Witten (for example in embodiment 3 and 6, using).Use from the Silicon stone that methylates
Figure GPA00001138960000142
R972 of Degussa as high dispersive hydrophobicity Silicon stone.(Aerosil R972 is the hydrophilic fumed silica, with the fumed silica of dimethyldichlorosilane hydrophobization, specific surface area is about 130m 2/ g, degree of methylating are 66%-75%).
Embodiment 1
0.14% Pradofloxacin trihydrate
1.0% clotrimazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 91g ℃ makes its dissolving.At about 22 ℃, the clotrimazole of suspension 1.0g and the dexamethasone acetate of 0.05g.The Pradofloxacin trihydrate of 0.14g is dissolved in the benzyl alcohol of 4g, and sneaks in the said suspension.Disperse polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 2
0.14% Pradofloxacin trihydrate
1.0% clotrimazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 95g ℃ makes its dissolving.At about 22 ℃, disperse Pradofloxacin trihydrate, the clotrimazole of 1.0g and the dexamethasone acetate of 0.05g, polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g of 0.14g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 3
0.14% Pradofloxacin trihydrate
1.0% clotrimazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% Polyethylene Glycol castor oil acid glyceride
(Glycerin-Polyethylenglykolricinoleat) (prepare by the Oleum Ricini of 1mol and the ethylene oxide of 35ml.This product comprises 83% hydrophobicity polyoxyethylene castor oil acid glyceride chemical compound and about 17% hydrophilic polyoxyethylene glycerol and Polyethylene Glycol)
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 91g ℃ makes its dissolving.At about 22 ℃, the clotrimazole of suspension 1.0g and the dexamethasone acetate of 0.05g.The Pradofloxacin trihydrate of 0.14g is dissolved in the benzyl alcohol of 4g, and sneaks in the suspension.Disperse polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 4
0.14% Pradofloxacin trihydrate
1.0% clotrimazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% Polyethylene Glycol castor oil acid glyceride
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 95g ℃ makes its dissolving.At about 22 ℃, be dispensed into the Pradofloxacin trihydrate of 0.14g, clotrimazole and the dexamethasone acetate of 0.05g, polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g of 1.0g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 5
0.14% Pradofloxacin trihydrate
1.0% bifonazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 91g ℃ makes its dissolving.At about 22 ℃, the bifonazole of suspension 1.0g and the dexamethasone acetate of 0.05g.The Pradofloxacin trihydrate of 0.14g is dissolved in the benzyl alcohol of 4g, and sneaks in the suspension.Be dispensed into polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 6
0.14% Pradofloxacin trihydrate
1.0% bifonazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 95g ℃ makes its dissolving.At about 22 ℃, be dispensed into the Pradofloxacin trihydrate of 0.14g, bifonazole and the dexamethasone acetate of 0.05g, polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g of 1.0g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 7
0.1% enrofloxacin
1.0% clotrimazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 91g ℃ makes its dissolving.At about 22 ℃, the clotrimazole of suspension 1.0g and the dexamethasone acetate of 0.05g.The enrofloxacin of 0.1g is dissolved in the benzyl alcohol of 4g, and sneaks in the suspension.Disperse polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 8
0.1% enrofloxacin
1.0% clotrimazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 95g ℃ makes its dissolving.At about 22 ℃, be dispensed into the enrofloxacin of 0.1g, clotrimazole and the dexamethasone acetate of 0.05g, polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g of 1.0g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 9
0.1% enrofloxacin
1.0% bifonazole
0.05% dexamethasone acetate
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 91g ℃ makes its dissolving.At about 22 ℃, the bifonazole of 1.0g and the dexamethasone acetate of 0.05g suspend.The enrofloxacin of 0.1g is dissolved in the benzyl alcohol of 4g, and sneaks in this suspension.Be dispensed into polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 10
0.1% enrofloxacin
1.0% bifonazole
0.05% dexamethasone acetate
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 95g ℃ makes its dissolving.At about 22 ℃, be dispensed into the enrofloxacin of 0.1g, the bifonazole of 1.0g and the dexamethasone acetate of 0.05g, polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 11
0.1% enrofloxacin
1.0% bifonazole
0.05% Ledercort A
4% benzyl alcohol
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 91g ℃ makes its dissolving.At about 22 ℃, the bifonazole of 1.0g and the Ledercort A of 0.05g suspend.The enrofloxacin of 0.1g is dissolved in the benzyl alcohol of 4g, and sneaks in the suspension.Disperse polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 12
0.1% enrofloxacin
1.0% bifonazole
0.05% Ledercort A
0.1% sorbic acid
0.05% polyoxyethylene, 20 Arlacel-80s
3.2% high dispersive hydrophobicity Silicon stone
Add to 100% medium chain triglyceride
The sorbic acid to 60 of the 0.1g of heating in the MCT of 95.5g ℃ makes its dissolving.At about 22 ℃, be dispensed into the enrofloxacin of 0.1g, bifonazole and the Ledercort A of 0.05g, polyoxyethylene 20 Arlacel-80s of 0.05g and the high dispersive hydrophobicity Silicon stone of 3.2g of 1.0g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.
Embodiment 13
5% toltrazuril
0.07% poloxamer (Pluronic PE 3100)
3% high dispersive hydrophobicity Silicon stone
Add to 100% paraffin, the thin liquid shape
The toltrazuril of 5g, the poloxamer of 0.07g and the high dispersive hydrophobicity Silicon stone of 3g are dispersed in the paraffin of 92g.Then, with homogenizer about 10 minutes of this suspension that homogenizes.

Claims (15)

1. amphiphilic species is used for the stable purposes that comprises the oil based fluids suspension of hydrophobicity Silicon stone.
2. according to the purposes of claim 1, it comprises as the ethylating chemical compound of the polyoxy of amphiphilic species.
3. according to the purposes of claim 1, it comprises the fluoroquinolone antibiotic as amphiphilic species.
4. medicine is included in the oil binder:
D) active component
E) hydrophobicity Silicon stone
F) the ethylating chemical compound of polyoxy, its concentration are 0.001-0.15 weight %.
5. according to the medicine of claim 4, it comprises the following substances as the ethylating chemical compound of polyoxy: poloxamer; Polyoxyethylene fatty acid glyceride; Polyoxyethylene sorbitan fatty acid ester; Polyoxyethylene fatty acid, or polyoxyethylene aliphatic alcohol.
6. according to the medicine of claim 4, it comprises fluoroquinolone.
7. according to the medicine of claim 6, it comprises enrofloxacin.
8. according to the medicine of claim 6, it comprises Pradofloxacin.
9. according to the medicine of claim 6, it comprises Marbofloxacin.
10. according to each medicine in the claim 4 to 9, it also comprises antifungal.
11. according to the medicine of claim 10, it comprises clotrimazole, miconazole or bifonazole.
12. according to each medicine in the claim 4 to 9, it also comprises adrenocortical hormone.
13. according to the medicine of claim 12, it comprises dexamethasone, betamethasone or triamcinolone.
14. according to the medicine of claim 4, it comprises triazine.
15. according to the medicine of claim 4, it comprises the following substances as the ethylating chemical compound of polyoxy: Polyethylene Glycol castor oil acid glyceride; Polyoxyethylene 20 Arlacel-80s; Polyethylene Glycol 15 hydroxy stearic acid esters, or hydroxyl polyethoxy dodecane.
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